Supportive health care measures instituted during childhood successfully prevent serious infections and many other life-threatening complications of sickle cell disease (SCD), resulting in improved survival to adulthood. This has, in part, shifted the demographics of SCD to include a growing proportion of young adults with chronic health impairments. While hematopoietic stem cell transplantation (HCT) has curative potential, very few individuals with SCD are treated by HCT, due in part to the toxicity of this treatment. Recently, advances in Human Leukocyte Antigen (HLA) typing techniques and supportive care have improved outcomes of HCT, particularly after unrelated donor HCT. Our overarching hypothesis is that HLA identical sibling and well- matched unrelated donor HCT in adults with severe SCD is feasible and has an acceptable safety profile with a 2-year event free survival of at least 80%. In order to test this hypothesis we propose the following specific aims: 1. Determine the safety and efficacy of HCT in young adults with severe SCD. 2. Measure the impact of donor hematopoiesis on functional outcomes and end-organ function. We will conduct a comparative clinical trial of HCT vs. standard supportive care in adolescents and young adults with SCD age 15-40 years of age. For this purpose we have organized an interdisciplinary group of investigators with expertise in HCT or SCD and a data-coordinating center very experienced in the conduct of clinical trials for the Blood and marrow transplant clinical trials network (BMT-CTN). This trial will compare outcomes after HCT to outcomes observed in those who receive standard supportive care, the first comparison of this kind in hemoglobinopathies. We will assign 60 patients who have an available suitably matched donor to the HCT arm. We will contemporaneously enroll 120-140 SCD who do not have an available suitable donor to a parallel comparison cohort. The primary endpoint is 2-year event free survival in the HCT patients. Secondary endpoints will compare functional outcomes including cardiopulmonary function, effort tolerance, health related quality of life, pain, organ function and SCD complications in those with or without an available donor, in a modified intent to treat analysis. HCT specific outcomes and complications, and lineage specific donor chimerism will also be studied. We will establish a long term follow up cohort of all eligible patients for the purpose of future studies of long term impact of HCT on outcomes in SCD. If successful, this study could establish the place of HCT in and broaden the therapeutic opportunities for the treatment of adults with severe SCD.